We propose to bring a well-established team of Investigators with diverse multidisciplinary backgrounds in virology, toxicology, clinical infectios disease, pharmacology, pharmaceutics, physiology, psychology/behavioral science, materials science, and biomedical engineering to develop a combination microbicide product formulated for delivery to both the vaginal and the colorectal compartments. The rationally designed products will include dual compartment gels (DuoGels) and Smart Suppositories that will function as delivery vehicles for two highly potent antiretroviral agents - tenofovir and IQP-0528. Our program will integrate in vitro and ex vivo evaluations of product efficacy, safety, pharmacokinetics and pharmacodynamics, as well as PK/PD/safety/efficacy evaluations in nonhuman primates and pre-Phase 1 safety and PK studies in humans. Our proposal also incorporates advancements in microbicide science, including the development of a novel in vitro method for determination of API dosing levels, behavioral studies extended to the rectal compartment and dual compartment products, and imaging and modeling that will enhance our ability to predict the interactions between formulated microbicide products, virus, biological matrices, and target fluids and tissue in the vagina and rectum. Our project will culminate in the creation of effective and acceptable, dual compartment use gels (DuoGels) and solid dosage vehicles (Smart Suppositories) for clinical development. We will create and apply advanced means to formulate and deliver these novel compounds (alone or in combinations) in coitally-dissociated ways. Pursuit of the two different delivery modalities (DuoGels versus Smart Suppositories) will account for both differences in microbicide functionality against HIV-1 and different product preferences amongst women. The time course of product development will include concomitant studies that define acceptability to women and men, so that cooptimization of biological functionality and behavioral acceptability is achieved. Through our industrial partnership with ImQuest Pharmaceuticals our methodology and products will have an immediate outlet to further clinical development.